Ample preclinical data suggests that grape seed extract (GSE) possesses anticarcinogenic properties. Grape seed contains high levels of polyphenols, including proanthocyanidins. These phytochemicals have been shown to modulate carcinogenic mechanisms, including inhibition of the cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) pathways, and inhibit tumor growth in animal models of lung cancer. While consumption of GSE is believed to promote good health and prevent cancer, actual clinical evidence is lacking. We therefore hypothesize that oral administration of GSE is safe, can favorably modulate mechanisms associated with lung tumorigenesis, and may be useful for lung cancer chemoprevention. To test these hypotheses, a single arm, dose escalation phase I lung cancer chemoprevention study of 3 months with an oral GSE will be conducted in 20 heavy active or ex-smokers (> 30 pack years of smoking). Aim #1: will determine the safety, tolerability and PK/PD of 3 months of GSE and the utility of bronchoscopic specimens for monitoring the bioactivity of GSE in the lung. Subjects will undergo serial fluorescence bronchoscopies with bronchoalveolar lavage (BAL), bronchial brushings, bronchial biopsies, along with collections of pre- and post-treatment blood and urine samples. A modified PK study will be performed by measuring grape seed proanthocyanidins (GSP) and metabolites in pre- and post-treatment samples. In addition, Pre- and post treatment plasma and BAL will be used in co-cultures with the nonsmall cell lung cancer cell (NSCLC) line A549 and the bronchial premalignant cell line 1198. The bioactivity of oral GSE in the lung will be assessed by comparing BAL co-culture with plasma co-cultures. The anti-neoplastic mechanisms of GSE will be assessed by comparing its bioactivity pre- and post-treatment as measured by modulations of: 1) proliferation index, COX-2 expression and PGE2 production in A549 and 1198 cells co-cultured with plasma and BAL; 2) Bronchial Ki-67 labeling index; 3) bronchial histopathology; 4) 15(S)-hydroxy-eicosatetraenoic acid (15-HETE), interleukin (IL)-6, IL-10, IL-12 and C-reactive protein (CRP); 5) cancer relevant, pathway specific gene expression profiles (GEP); and 6) epigenetic profiles assessed by micro(mi) RNA expression in BAL cells, bronchial brushing and biopsies. Aim #2: will characterize the roles of mir-19a, mir-19b, and mir-106b in mediating the anti-neoplastic effects of GSE and examine the potential of plasma mir-19a, -19b, -106b as surrogate endpoint biomarkers (SEBM) for therapeutic monitoring. In preliminary studies, we have identified mir-19a, mir-19b, and -106b as the most significantly down-regulated miRNAs by GSE in A549 and H1299 cells. These miRNAs are well known oncomirs in lung cancer and are among the major plasma miRNAs identified to be predictors of lung cancer development in a recent report. Therefore, we will measure these miRNA levels in plasma pre- and post-treatment to determine their utility as SEBM for GSE treatment. Findings from the study will provide important insights into the feasibility and mechanistic effects of GSE against lung cancer, help identify SEBM and set the stage for future clinical trials.